The de-ubiquitinase UCH-L1 is a novel oncogene that is frequently expressed in human B-cell malignancies of varying histology. It is unclear, however, if UCH-L1 contributes to the pathogenesis of al malignancies in which it is expressed, and what molecular mechanism underlies this oncogenic activity. Our long-term goal is to understand the role of de-ubiquitinating enzymes in regulating the pathogenesis of cancer. As the next step towards attainment of this goal, the overall objective of this proposal is to determine the extent of involvement of UCH-L1 in the pathogenesis of B-cell malignancies and to identify the direct molecular interactions involved in its stimulating effects on the Akt signaling pathway. Specifically, in this proposal we test our central hypothesis that UCH-L1 is an oncogene involved in the pathogenesis of a range of B-cell cancers through a novel mechanism of regulating mTOR/Akt signaling. Our rationale for the proposed experiments is that an improved understanding of UCH-L1 in the pathogenesis of B-cell cancers we will provide new insight into the biology of these prevalent diseases, and will lead to an appreciation of UCH-L1 as a novel regulatory protein in the mTOR/Akt signaling pathways. Based on strong preliminary data, we will test our hypothesis through the following three specific aims: 1) Determine the impact of UCH-L1 on the development of cancer in vivo;2) Determine the requirement for UCH-L1 in B-cell malignancy;3) Identify the mechanism(s) by which UCH-L1 promotes B-cell cancers. In the first aim, we will mate Uchl1 transgenic mice with models of biologically distinct B-cell malignancies to understand the contribution of UCH-L1 to the pathogenesis of these diseases. In the second aim, we will utilize UCH-L1 knockout mice and RNAi technology to investigate the requirement for UCH-L1 expression in the initial development, and ongoing survival of established cancers. In the third aim we will employ mouse genetic and cellular biochemical studies to study the molecular mechanism(s) by which UCH-L1 regulates the mTOR/Akt pathway, and to determine if this effect is central to the oncogenic properties of UCH-L1. The approach is innovative because it explores a previously unknown signaling relationship between UCH-L1 and the mTOR/Akt pathway and at the same time establishes the in vivo relevance of this link in the context of B-cell malignancy. The proposed research is significant because it is expected to vertically advance our understanding of the mechanisms behind the development and maintenance of common human cancers. The results of these experiments may ultimately provide much needed information regarding the biology and therapy of these diseases. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because B-cell lymphoma and multiple myeloma affect tens of thousands of people in the United States each year, and the results of our work may immediately suggest a novel therapeutic target for these conditions. As our work pertains to the biology of other pathways that are targeted by drugs currently in early phase clinical trials, our results may aid in the prediction of patients who may benefit most from these treatments. Therefore, the proposed research is highly relevant to the parts of the NIH's mission that are charged with reducing the burden of cancer.